Arsenite-induced Cdc25C degradation is through the KEN-box and ubiquitin–proteasome pathway

doi:10.1073/pnas.032428899

Arsenite-induced Cdc25C degradation is through the KEN-box and ubiquitin–proteasome pathway

^*Health Effects Laboratory Division, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Morgantown, WV 26505; and ^‡Howard Hughes Medical Institute and Department of Cell Biology and Physiology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8228, St. Louis, MO 63110-1093

Edited by Marc W. Kirschner, Harvard Medical School, Boston, MA, and approved December 3, 2001 (received for review August 14, 2001)

Abstract

Arsenite is a known human carcinogen that induces tumorigenesis through either a genotoxic or an epigenetic mechanism. In this study, the effect of arsenite on cell cycle regulation and the mechanisms that contribute to this effect were investigated. Treatment of the cells with arsenite suppressed cell proliferation and reduced cell viability in a dose- or time-dependent manner. Analysis of cell cycle profile and cell cycle regulatory proteins indicated that arsenite arrested the cell cycle at G₂/M phase, partially through induction of cell division cycle 25 (Cdc25) isoform C (Cdc25C) degradation via ubiquitin–proteasome pathways. Mutation of the putative KEN box within the region 151 to 157 of human Cdc25C or treatment of the cells with a peptide competitor encompassing the KEN box partially inhibited arsenite-induced ubiquitination of Cdc25C. Thus, these results indicate that the regulated ubiquitination of Cdc25C may be involved in the arsenite-induced proteolytic down-regulation of Cdc25C activity in the G₂/M phase of the cell cycle and suggest a link between cell cycle and the carcinogenic effects of arsenite.

Footnotes

↵ † To whom reprint requests should be addressed. E-mail: lfd3{at}cdc.gov .
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations:

Cdk,

cyclin-dependent kinases;

Cdc25,

cell division cycle 25;

APC,

anaphase promoting complex;

D box,

destruction box;

Chk,

checkpoint kinase